The retinoblastoma (Rb) protein is a key cell-cycle regulator disrupted in many cancers, and thus a molecular picture of Rb function is important for understanding mechanisms of tumorigenesis. Rb binds members of the E2F transcription factor family and thereby inhibits the expression of genes required for cell-cycle progression. Multiple phosphorylations of Rb dissociate Rb-E2F complexes, and this process is regulated by Cyclin-dependent kinases (Cdks) and protein phosphatase 1 (PP1). The objective of this proposal is to understand in molecular detail how phosphorylation disrupts Rb-E2F binding and how Cdks and PP1 phosphorylate and dephosphorylate Rb. A number of biophysical and structural techniques including x-ray crystallography, nuclear magnetic resonance, mass spectrometry, and calorimetry, will be applied to characterize the protein interactions of Rb with E2F, Cdks and PP1.

Public Health Relevance

Tumor cells invariably have defects in the biochemical mechanisms that regulate cell growth and division, so understanding how these processes work is vital to understanding cancer. This proposal aims to develop a molecular picture of how a cell-cycle regulator known as the retinoblastoma protein functions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132685-03
Application #
7825327
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Knowlton, John R
Project Start
2008-08-19
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$303,302
Indirect Cost
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Liban, Tyler J; Medina, Edgar M; Tripathi, Sarvind et al. (2017) Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family. Proc Natl Acad Sci U S A 114:4942-4947
McGrath, Denise A; Fifield, Bre-Anne; Marceau, Aimee H et al. (2017) Structural basis of divergent cyclin-dependent kinase activation by Spy1/RINGO proteins. EMBO J 36:2251-2262
Ishak, Charles A; Marshall, Aren E; Passos, Daniel T et al. (2016) An RB-EZH2 Complex Mediates Silencing of Repetitive DNA Sequences. Mol Cell 64:1074-1087
Pye, Cameron R; Bray, Walter M; Brown, Elise R et al. (2016) A Strategy for Direct Chemical Activation of the Retinoblastoma Protein. ACS Chem Biol 11:1192-7
Liban, Tyler J; Thwaites, Michael J; Dick, Frederick A et al. (2016) Structural Conservation and E2F Binding Specificity within the Retinoblastoma Pocket Protein Family. J Mol Biol 428:3960-3971
Marceau, Aimee H; Felthousen, Jessica G; Goetsch, Paul D et al. (2016) Structural basis for LIN54 recognition of CHR elements in cell cycle-regulated promoters. Nat Commun 7:12301
Guiley, Keelan Z; Liban, Tyler J; Felthousen, Jessica G et al. (2015) Structural mechanisms of DREAM complex assembly and regulation. Genes Dev 29:961-74
Burke, Jason R; Liban, Tyler J; Restrepo, Tamara et al. (2014) Multiple mechanisms for E2F binding inhibition by phosphorylation of the retinoblastoma protein C-terminal domain. J Mol Biol 426:245-55
Dick, Frederick A; Rubin, Seth M (2013) Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 14:297-306
Schachter, Miriam Merzel; Merrick, Karl A; Larochelle, Stephane et al. (2013) A Cdk7-Cdk4 T-loop phosphorylation cascade promotes G1 progression. Mol Cell 50:250-60

Showing the most recent 10 out of 18 publications